Structure-activity studies of a peptide derived from Activity Dependent Neurotrophic Factor (ADNF), a novel protein released from glial cells by vasoactive intestinal peptide (VIP), revealed that complete survival- promoting activity was retained with a nine amino acid peptide (ADNF-9). A panel of thirty test peptides was utilized to establish the loci and identity of critical amino acid residues. In dissociated cell cultures from the rat cerebral cortex, ADNF-9 was found to exhibit neuroprotective actions to prevent neuronal cell death associated with excitotoxicity and gp120, the envelope protein from the human immunodeficiency virus. Further structural studies on peptides from protease digests of intact ADNF indicated close homology to a recognized intracellular stress protein. Radiolabeled gp120 administered to pregnant rats was recovered in the brains of fetuses. Both intact gp120 and its neurotoxic fragments were found to preferentially accumulate in fetal brain two days after injection. Treatment of whole cultured mouse embryos with gp120 produced a dose-dependent inhibition of growth as measured by somite number and image analysis of whole body size. The growth deficits produced by gp120 were prevented by co-treatment with either VIP or a VIP analogue, peptide T. A novel VIP agonist (SNV) was synthesized and shown to be neuroprotective against the neuronal cell killing action of beta amyloid peptide, a toxic substance associated with Alzheimer's disease. SNV was shown to preferentially interact with VIP binding sites that were insensitive to GTP in the developing rodent brain and that were independent of cAMP action. SNV, like VIP, produced significant increases in growth in early post-implantation embryos. VIP-mediated increases in mitosis in embryos was associated with increased cyclin A expression as measured by reverse transcriptase polymerase chain reaction.